The primary emphasis of the group is ovarian function and disease, and through major collaborations we also study uterine leiomyoma and breast cancer. Using ovarian toxicants such as the phthalates and glycol ethers, and ovarian carcinogens such as dioxins and other furans, we have defined cellular and molecular pathologies that contribute to fundamental lesions in ovarian function and towards the development of cancer. For example, these studies are the first to show that the most common environmental contaminant, di-2-ethylhexyl phthalate (DEHP) and its active metabolite (MEHP) suppresses estradiol production in ovarian granulosa cells by decreasing transcription of aromatase through the PPARalpha and gamma receptors. Research efforts continue to determine how prostaglandins function in reproductive health and disease. Specially, we have examined expression of cyclooxygenase 1 and 2 in human ovarian cancers and ovarain cancer cell lines. Prostaglandins and specificially COX-2 regulated prostaglandins may play a role in uterine leiomyoma. Current evidence suggest that this tumor has characteristics of well-differentiated uterine smooth muscle cells of pregnancy. Data from our laboratory using animal models (Eker Rat) and cell culture experiments (Eker rat-derived uterine leiomyoma cells and human leiomyoma and normal myometiral cells) suggest further that these tumor cells have features of smooth muscle just prior to the onset of parturition. However, the tumor cells may lack the ability to induce COX-2 necessary to induce either apoptosis or dedifferentiation as occurs in parturition. Thus, leiomyoma cells are unresponsive to this signaling pathway and thereby persist in a cancerous phenotype. The growth of uterine leiomyoma is under further investigation using magnetic resonance imaging (MRI) in a clinically relevant population of women. We test the hypotheses that uterine leiomyomas are heterogeneous in terms of their growth characteristics and in their clinical symptoms or outcomes and that differences in leiomyoma growth dynamics can be discriminated by molecular markers and cellular phenotypes. The specific aims are to: (1) compare leiomyoma growth as a function of multiplicity and location by MRI analysis in women with high risk for surgical intervention (i.e., hysterectomy/myomectomy); (2) examine the relationship between leiomyoma growth and clinical symptoms or outcome; (3) identify molecular, cellular, and pathological characteristics of the leiomyomas with differing growth dynamics; and (4) examine endocrinological parameters and lifestyle factors related to differential growth dynamics of uterine leiomyomas. Participants will include 300 ethnically diverse women of reproductive age (18-45 years) with uterine leiomyoma.